P838: EXOSOME MIRNAS PROFILING IN SERUM AND PROGNOSTIC EVALUATION IN PATIENTS WITH MULTIPLE MYELOMA
Authors: Teng Fang, Hao Sun, Mu Hao, Lugui Qiu, Xiyue Sun, Guoqing Zhu, Yi He, Lixin Gong, Peixia Tang, Zhen Yu, Lanting Liu, Shiyi Xie
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Multiple Myeloma (MM) is an incurable hematological malignancy characterized by the clonal expansion of malignant proliferation of plasma cells in the bone marrow (BM). Tightly crosstalk between the bone marrow microenvironment and MM cells plays pivotal roles in the occurrence and progression of MM. MicroRNAs (miRNAs) carried by exosomes play pivotal roles in the crosstalk between cell components in the tumor microenvironment (TME). Aims: Our study aimed to identify the expression profile of exosomal miRNAs (exo-miRNAs) in the serum of MM patients and investigate the regulation network and their potential functions by integrated bioinformatics analysis. Methods: Exosomes in serum from 19 newly diagnosed multiple myeloma patients and 9 healthy donors were isolated and the miRNA profile was investigated by small RNA sequencing. Differential expression of exo-miRNAs was calculated and target genes of miRNAs were predicted. CytoHubba was applied to identify the hub miRNAs and core target genes. The LASSO Cox regression model was utilized to develop the prognostic model, and the ESTIMATE immune score was calculated to investigate the correlation between the model and immune status in MM patients. Results: In our study, 313 differentially expressed serum exo-miRNAs between MM patients and HD were clarified. GO analysis of target genes of differential miRNAs showed that these target genes are mainly involved in the critical biological processes related to MM pathogenesis such as proteasome-mediated ubiquitin-dependent protein catabolic process, and regulation of protein stability, indicating the indispensable roles of these miRNAs in MM pathogenesis. Top six hub differentially expressed serum exo-miRNAs (hsa-miR-4728-5p, miR-455-3p, hsa-miR-6779-5p, hsa-miR-124-3p, hsa-miR-615-3p, and hsa-miR-7106-5p) were identified. 513 target genes of six hub exo-miRNAs were confirmed to be differentially expressed in MM cells in Zhan Myeloma microarray dataset. Functional enrichment analysis indicated that these target genes were mainly involved in mRNA splicing, cellular response to stress, and the deubiquitination process. Thirteen core exo-miRNA target genes were applied to create a novel prognostic signature to facilitate the risk stratification of MM patients（Fig.1A）. Due to the prognostic stratification by the thirteen core genes signature identified above, two groups of MM patients with diverse outcomes were recognized. The high-score patients identified by thirteen core genes signature displayed a higher 70 high-risk gene set (UAMS-70) score, as well as the 56 drug-resistance genes set score, which might partly explain their inferior outcomes（Fig.1B-C）. Additionally, our results suggest that the thirteen core genes signature model was highly correlated with the status of the immune microenvironment, and patients in the low-score group had higher immune cell infiltration levels（Fig.1D）. Besides, patients in the high-risk group displayed lower HLA family gene expression（Fig.1E）. Summary/Conclusion: Our study comprehensively investigates the exo-miRNA profiles in MM patients. A novel prognostic signature was constructed to facilitate the risk stratification of MM patients with distinct outcomes.Keywords: Multiple myeloma, Prognosis, liquid biopsy